Compound screening to repurpose FDA-approved drugs against SARS-CoV-2 catalytic enzymes

Therapeutic options for combating the COVID-19 pandemic are urgently needed. FDA-approved drugs and many existing experimental drugs have already been tested in humans, and their pharmacology and potential toxicity are known. Discovering which of these compounds can be effectively repurposed as antiviral agents against SARS- CoV-2 would allow them to be advanced to clinical trials. We propose to screen a library of existing FDA-approved drugs against ten intracellular catalytic SARS-CoV-2 protein targets, with the goal of identifying drugs that disrupt viral protein function and diminish viral viability. The approach of inhibiting catalytic viral enzymes has ample precedent in other viral systems, such as HIV and Hepatitis Virus C, to serve as a very successful therapeutic strategy. Our project consists of three main steps. First, initial screening will be performed computationally to reduce the number of compounds (10,000+) and protein targets to an experimentally manageable number, and to establish priorities for the subsequent workflow. Computational screening will include performing enhanced sampling molecular simulations of the protein targets to allow potentially druggable cryptic binding sites to emerge, followed by compound docking to those sites to identify possible ligands. Second, the target proteins will be expressed and purified, and activity assays will be developed. Third, prioritized compounds in the Johns Hopkins Drug Library will be screened against the purified target proteins to identify those that exhibit antiviral activity.\n